Imines protonated

Analysis of the kinetics of this catalysis points to the protonated imine as the key intermediate. 

Because the imine is much more basic than the carbonyl compound, it is more extensively protonated at any given pH than is the aldehyde. The protonated imine is also more reactive as an electrophile than the neutral aldehyde. There are four possible electrophiles in the system ... 

The protonated imine is the dominant reactive form. Although the protonated aldehyde is more reactive, its concentration is very low because it is much less basic than the imine or the reactant hydroxylamine. On the other hand, even though the aldehyde may be present in a greater concentration than the protonated imine, its reactivity is sufficiently less that the iminium ion is the major reactant. ... 

This approach finds experimental support in FTIR measurements of the oxidation of PANI in organic solvents which indicate an anion intercalation mechanism for the second oxidation step. However, the IR findings may also be interpreted as support for the formation of a protonated imine structure... 

These reactions are catalyzed by ammonium acetate, the function of which is to generate protonated imines (322). Under mild reaction conditions, condensation of a- hydroxyamino-oximes with acetone dialkylketals takes place. The procedure can be successfully applied in cases where direct condensation with acetone... 

These results also indicate that the protonation of the imine group is important for the reaction. In the o-OH and p-OH isomers, resonance between the protonated imine and quinoido species would contribute in facilitating the protonation of the imine portion (Scheme 5.17). In the m-OH isomer, however, no such resonance contribution is possible. Thus, the poor additive effect of phenol in the reaction of N-benzylideneaniline with the acylzirconocene chloride (entry 1, Table 5.3) might imply less efficient protonation of the imine, as in the case of the m-OH isomer (Scheme 5.16). 

Protonated imines are effective dienophiles. Thus in the reaction of methyl glyoxylate with the hydrochloride 127 of alanine methyl ester in the presence of cyclopentadiene, a mixture of hydrochlorides of the exo- and ewrfo-adducts 128-131 was formed (equation 69). The diastereomeric ratio of the exo-compounds was 83 1761. 

This compound removes a proton from the carboxylic acid, producing a cation that is readily attacked by the carboxylate nucleophile across one of the C-N double bonds - the protonated imine behaves as a good electrophile (see Section 7.7.1). The product is now an activated ester (an O-acylisourea) that can be attacked by any available nucleophile. The amino group of the second amino acid derivative provides the nucleophile, resulting in expulsion of a very stable urea as the leaving group, and production of the... 

The majority of transformations reported within the literature using the concept of LUMO energy lowering iminium ion activation have nsed secondary amines as the catalyst. Under the aqueous acidic reaction conditions inherent to this mode of activation it is also possible to nse primary amines as efficient catalysts where the active species is the protonated imine 141 (Fig. 13). Althongh this is a somewhat less explored avenne of research, initial results suggest it will become an equally fruitful area with broad application. 

In 2003, we reported a multicomponent approach toward highly substituted 2H-2-imidazolines (65) [157]. This 3CR is based on the reactivity of isocyano esters (1) toward imines as was studied in detail by Schollkopf in the 1970s [76]. In our reaction, an amine and an aldehyde were stirred for 2 h in the presence of a drying agent (preformation of imine). Subsequent addition of the a-acidic isocyanide 64 resulted in the formation of the corresponding 2//-2-imidazolines (65) after 18 h in moderate to excellent yield. The mechanism for this MCR probably involves a Mannich-type addition of a-deprotonated isocyanide to (protonated) imine (66) followed by a ring closure and a 1,2-proton shift of intermediate 68 (Fig. 21). However, a concerted cycloaddition of 66 and deprotonated 64 to produce 65 cannot be excluded. 

The mechanism for the uncatalyzed decarboxylation of P-ketoacids had previously been established by Bredt and by Pedersen (Bredt, 1927 Pedersen, 1929 1936 Westheimer and Jones, 1941). The acid loses C02 to form the enol of the product, which subsequently ketonizes. The idea behind Pedersen s mechanism for aniline catalysis is that nitrogen is more basic than oxygen, and so could be protonated more readily the protonated imine would provide a better electron sink than the ketone. Although Pedersen offered little or no experimental support for his hypothesis, it provided a basis in physical organic chemistry for the mechanism of the corresponding enzymic process. 

This enzyme catalyzes the decarboxylation of acetoacetate to acetone and carbon dioxide. The nonenzymatic reaction involves the expulsion of a highly basic eno-late ion at neutral pH (equation 2.36), but the enzymatic reaction circumvents this by the prior formation of a Schiff base with a lysine residue. The protonated imine is then readily expelled. 

The aldol condensation and the reverse cleavage reaction catalyzed by these enzymes both involve a Schiff base. The cleavage reaction is similar to the acetoac-etate decarboxylase mechanism, with the protonated imine being expelled. The condensation reaction illustrates the other function of a Schiff base, the activation of carbon via an enamine (equation 2.40). 

Electrochemical reduction of imines (25 Schiff bases) in acidic media proceeds via the iminium species, i.e. the protonated imine (26) (Scheme 5)29. Since 26 bears a positive charge, it is very easily reduced, so much so that the resulting neutral radical (27) is formed at a potential positive of its reduction potential. The products are therefore derived from 27 rather than the corresponding carbanion (28). This stands in contrast with the electrochemical behavior of imines in neutral media, where 27 is immediately reduced to 2830. Thus, cathodic reduction of /u. s-irnincs of 1,2-diamines (29) in DMF containing methanesulfonic acid affords tetrahydropyrazines (equation 13)31. A similar reaction can... 

One published synthesis of this amine 17 is by reductive animation.2 Note that it is not necessary, nor usually desirable, to isolate the rather unstable imine as reduction with NaB(CN)H3 or NaB(OAc)3H occurs under the conditions of imine formation.3 Since the imine is in equilibrium with the starting materials, slightly acidic conditions must be used so that the protonated imine is reduced more rapidly than the aldehyde or ketone. These two reducing agents are stable down to about pH 5. 

The product of the elimination step is a protonated imine, the conjugate acid of the final product. The proton is transferred to a solvent molecule in an acid-base reaction to produce the imine. 

The Strecker synthesis can form a large number of amino acids from appropriate aldehydes. The mechanism is shown next. First, the aldehyde reacts with ammonia to give an imine. The imine is a nitrogen analogue of a carbonyl group, and it is electrophilic when protonated. Attack of cyanide ion on the protonated imine gives the a-amino nitrile. This mechanism is similar to that for formation of a cyanohydrin (Section 18-14), except that in the Strecker synthesis cyanide ion attacks an imine rather than the aldehyde itself. 

The electrophilic protonated imine reacts with nucleophilic hydroxylamine. 

The pathway involving cyclization of a protonated migrating group provides a very appealing alternative to the fragmentation-recombination pathway. Given the lack of evidence for imine formation, it is interesting to note that the formation of a protonated imine (14-H ) in the model system can alternatively arise formally as the result of removal of a hydride ion from the parent (saturated) system (12), aminopropyl (path e. Scheme 9). 

At a somewhat lower pH, as the fraction of protonated imine increases (typical pK values are 6-7) and the concentration of hydroxide decreases, the attack of water on the protonated imine becomes important, as shown in Eq. (27). 

A variety of reducing agents have been used for the conversion of imines to amines.The examples in equations (50) and (51) are typical. The relatively slow destruction of sodium cyanoboro-hydride in slightly acid aqueous solutions allows the process of imine formation to be carried out simultaneously with reduction. Apparently, the protonated imine is the species that is reduced and this process occurs significantly faster than reduction of the original carbonyl compound by this reagent. A recent report by Nose indicated that diborane in methanol will reduce only imines and no other functionality. Apparently, the diborane reacts rapidly with methanol to form a derived reagent. 

Answer The most reactive is the protonated aldehyde. The protonated imine is next, for it is slightly more stable. The least reactive is the neutral imine because the anion formed upon nucleophilic attack is more basic than the anion formed upon attack of the neutral aldehyde. 

The photochemical cyclisations of the imines (46) is a typical 6e process and irradiation in the presence of HBF4 gives conversion into the corresponding cyclic compounds. The yields obtained from the processes are moderate and there is little doubt that cyclisation involves the protonated imine. Several products are formed on irradiation of the naphthylalanine derivatives (47). ... 

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